Field of the Invention
The present invention is directed to methods for reducing systemic absorption of therapeutic compounds or agents while enhancing efficiency of delivery and targeting of intranasal administration of such compounds or agents to the central nervous system generally and preferentially to one or more specific regions of the central nervous system. More specifically, use of ultrasound technology in conjunction with intranasal delivery of a therapeutic compound, or pharmaceutical composition, wherein the intranasal delivery is preferably to the upper one third of a patient's nasal cavity, thereby reducing therapeutic compound or agent absorption into the blood while targeting the therapeutic compound to one or more specific regions of the central nervous system.
Description of the Related Art
It is known that intranasal administration of therapeutic compounds or agents may, in some cases, increase the effectiveness of certain therapeutic compounds or agents in bypassing the blood-brain barrier (BBB) and delivering the compound or agent directly to the Central Nervous System (CNS). Thus, intranasal administration of therapeutic compounds may allow increased prevention and/or treatment of certain diseases or conditions.
Intranasal delivery, preferably to the upper third of a patient's nasal cavity, is a means of bypassing the BBB to administer therapeutic compounds and/or agents directly to the CNS. Evidence exists that intranasal treatment improves, i.e., prevents and/or treats, a variety of neurological and psychiatric disorders, e.g., stroke, in animals. When delivered to the upper third of the patient's nasal cavity, the vast majority of many administered therapeutic compounds and/or agents which reach the CNS from the nasal mucosa, bypass the BBB. This basic methodology is discussed and described in U.S. Pat. No. 5,624,898 to Frey II entitled Method for Administering Neurologic Agents to the Brain, the entire contents of which are hereby incorporated by reference. This intranasal administration technique is a vast improvement over systemic administration methods such as intravenous and oral administration of drugs which generally cannot cross the BBB to reach their targets within the CNS. In addition, Frey's intranasal method is a significant improvement over the general inhalation methods which target the lower two-thirds of the patient's nasal cavity. Both the systemic and general intranasal method targeting the lower two-thirds of the nasal cavity result in a very large, unwanted and potentially dangerous systemic exposure to the administered drug or therapeutic. The present invention addresses, inter alia, this general intranasal problem as well as improves the efficiency of Frey's upper one-third intranasal administration and improves the targeting of therapeutics to specific areas of the CNS.
General inhalation methods to the lower two-thirds of the nasal cavity delivered by, e.g., nasal spray bottles, on the other hand, result in a large amount of systemic absorption and exposure, with a very small amount, i.e., less than 5%, making the tortuous journey around the turbinates to the upper third of the nasal cavity and further bypassing the BBB to reach the CNS. The present invention can improve even this inefficient procedure by using focused ultrasound energy to improve the delivery efficiency to the CNS generally as well as providing a focused delivery to at least one target region within the CNS
Intranasal delivery of therapeutic compounds, both to the patient's nasal cavity generally with the majority of the administered compound(s) delivered to the lower two-thirds of the nasal cavity, and to the upper third of the nasal cavity specifically, comprise known procedures. Delivery and administration to the upper third of the nasal cavity, is very effective in administering the subject compounds or agents to the desired target, i.e., the CNS, without significant systemic exposure, though some systemic exposure does occur as is further discussed below. The present invention uses focused ultrasound energy to improve the delivery efficiency of intranasal delivery administration techniques to the CNS generally as well as providing a focused delivery to at least one target region within the CNS, as opposed to non-target systemic organs and other body parts.
Unwanted systemic exposure of therapeutics used to treat CNS diseases create several problems. The systemic metabolism greatly reduces the bioavailability of any agent and/or compound exposed to the non-CNS system. This reduction of bioavailability is increased by unwanted plasma protein binding of the agent and/or compound. As a result, only a small amount of the active therapeutic agent and/or compound actually reaches the CNS. Because of these, inter alia, issues, the actual dose that must be administered in order to achieve a therapeutic dose in the targeted CNS is far larger than the therapeutic dosing. As a consequence, a relatively large concentration of the agent(s) and/or compounds(s) is in the system and will affect non-target systemic organs and systems. This can create unwanted and often dangerous side effects on these non-target organs and systems.
We have addressed the efficiency needs in patent application Ser. No. 12/134,385 to Frey II, et al., entitled “Pharmaceutical Compositions and Methods for Enhancing Targeting of Therapeutic Compounds to the Central Nervous System, the entire contents of which are hereby incorporated by reference, and wherein a vasoconstrictor is administered to the patient's nasal cavity either just prior to, or in combination with, administration of a pharmaceutical composition comprising a therapeutic compound(s) and/or agent(s). The efficiency of the direct administration of the pharmaceutical compound to the CNS, with concomitant reduction of systemic exposure of the pharmaceutical compound is remarkable.
However, we have also determined that at times very high concentrations of an intranasally administered therapeutic compound and/or agent are found in the system. For example, in Dhuria et al. (2009) JPET 328(1):312-320, we report that very high concentrations of intranasally administered drug are found in the walls of the carotid artery (83 nM) relative to the blood (3.4 nM) and brain (approximately 1 nM). In the presence of a vasoconstrictor in the formulation, there is an even higher concentration of drug in the walls of the carotid relative to the blood or brain. Similarly, in the walls of the basilar artery and circle of willis blood vessels, there are higher concentrations of drug following intranasal delivery than in the blood or brain as reported by Thome et al. (2004) Neurosci. 127:481-496. It is known that intranasal drugs and/or therapeutics distribute throughout the CNS through the perivascular spaces of blood vessels of the cerebrovasculature once they reach the CNS by traveling along the olfactory and trigeminal neural pathways. The present invention can aid in moving these intranasally delivered therapeutic agents and/or compounds from the perivascular spaces to the targeted CNS region(s) where the ultrasound is focused. This is in addition to the present invention's utility in moving bloodstream-borne therapeutic agent(s) and/or compound(s) from the bloodstream through the BBB to one or more ultrasonic-energy targeted CNS regions. In addition, the concentration of the therapeutic agent and/or compound is increased at the target region(s) of the CNS where the ultrasound energy is focused.
Therefore, even the most efficient of the known intranasal delivery systems and methods are subject to efficiency improvements. In particular, therapeutic compounds may be absorbed into the blood and/or delivered to peripheral (non-target) tissues, thus reducing delivery of the compound to the target. It would be desirable to reduce absorption of therapeutic compounds or agents into the blood and delivery to non-target or peripheral tissues not located in the CNS.
Thus, it would be desirable to increase the efficiency of uptake of agents and/or compounds into the CNS using general intranasal administration techniques wherein the therapeutic agent and/or compound is administered primarily to the lower two-thirds of the patient's nasal cavity.
It would be further desirable to increase the efficiency of uptake of agents and/or compounds into the CNS using intranasal administration techniques wherein the therapeutic agent and/or compound is administered primarily to the upper one third of the patient's nasal cavity.
It would be still further desirable to increase the targeting ability within the CNS for therapeutic agent(s) and/or compound(s) delivered either by general inhalation methods, i.e., to the lower two-thirds of the nasal cavity, or by delivering the agent(s) and/or compound(s) directly to the CNS by administration to the upper one third of the patient's nasal cavity.
Given the situation described above there is a need for, inter alia: increasing efficiency of intranasal administration of therapeutic compounds and/or agents to the CNS; increased targeting of intranasal delivery of therapeutic compounds and/or agents to target regions within the CNS; and decreasing absorption of the intranasally administered therapeutic compounds and/or agents to the blood and peripheral tissues. The present invention addresses these, among other, needs.